66
Electrolyte & Blood Pressure 4:66-71, 2006
2)
Hypernatemia : Successful Treatment
Soo Wan Kim, M.D.
Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
Hypernatremia reflects a net water loss or a hypertonic sodium gain, with inevitable hyperosmolality.
Severe symptoms are usually evident only with acute and large increases in plasma sodium
concentrations to above 158-160 mmol/l. Importantly, the sensation of intense thirst that protects against
severe hypernatremia in health may be absent or reduced in patients with altered mental status or with
hypothalamic lesions affecting their sense of thirst and in infants and elderly people. Non-specific
symptoms such as anorexia, muscle weakness, restlessness, nausea, and vomiting tend to occur early.
More serious signs follow, with altered mental status, lethargy, irritability, stupor, and coma. Acute
brain shrinkage can induce vascular rupture, with cerebral bleeding and subarachnoid hemorrhage.
However, in the vast majority of cases, the onset of hypertonicity is low enough to allow the brain to
adapt and thereby to minimize cerebral dehydration. Organic osmolytes accumulated during the adaptation to hypernatremia are slow to leave the cell during rehydration. Therefore, if the hypernatremia is
corrected too rapidly, cerebral edema results as the relatively more hypertonic ICF accumulates water.
To be safe, the rate of correction should not exceed 12 mEq/liter/day.
Key Words : Hypernatremia, Cell volume regulation, Diabetes insipidus
Hypernatremia, defined as a rise in the serum sodium concentration to a value exceeding 145 mmol per
Pathophysiology
liter, is a common electrolyte disorder. Because sodium
is a functionally impermeable solute, it contributes to
As in other types of cells, hypertonically stressed
tonicity and induces the movement of water across
brain cells regulate their volume initially by the rapid
cell membranes. Therefore, hypernatremia invariably
uptake of electrolytes3). With a prolonged elevation of
denotes hypertonic hyperosmolality and always causes
plasma osmolality, however, most excess electrolytes
cellular dehydration, at least transiently. Although
in the brain are replaced by organic solutes. These
correction of transient increases in plasma osmolality
solutes
is usually well tolerated, correction of chronic plasma
osmoles” because they were unidentified and thought
hypertonicity with rehydration therapy may be accom-
to be produced by the brain cells themselves . Studies
panied by brain swelling, herniation, and death1). The
in animals and cultured cells5) have revealed that
clinical differences between acute and chronic osmolar
idiogenic osmoles are the same organic osmolytes used
disorders can be understood through a consideration of
by all organisms for volume regulation. The most
the different mechanisms by which cells in the brain
important organic osmolytes in the mammalian brain
regulate their volume in response to brief and sus-
include myo-inositol, taurine, glycerylphosphorylcho-
2)
tained osmotic challenges .
have
historically
been
termed
“idiogenic
4)
line, and betaine, which are accumulated primarily by
uptake from extracellular fluids through the activation
Correspondence author : Soo Wan Kim, M.D.
Department of Internal Medicine, Chonnam National University
Medical School, Gwangju, Korea
Tel : 062)220-6272, Fax : 062)220-8578
Email : [email protected]
of sodium-dependent cotransporters5).
Beginning on the first day of the hypernatremia,
brain volume is largely restored due noth to water
SW Kim : Hypernatemia : Successful Treatment
67
movement from the cerebrospinal fluid into the brain
(thereby increasing the interstitial volume)5) and to the
Causes of hypernatremia
uptake of solutes by the cells (thereby pulling water
5-7)
. The
Hypernatremia represents a deficit of water in
latter response involves an initial uptake of sodium
relation to the body’s sodium stores, which can result
and potassium salts, followed by the later accumula-
from a net water loss or a hypertonic sodium gain
tion of osmolytes, which in animals consists primarily
(Table 1). Net water loss accounts for the majority of
of myo-inositol and the amino acids glutamine and
cases of hypernatremia1). It can occur in the absence
glutamate6, 7). Myo-inositol is taken up from the ex-
of a sodium deficit (pure water loss) or in its presence
tracellular fluid via an increase in the number of
(hypotonic fluid loss). Hypertonic sodium gain usually
sodium-myo-inositol cotransporters in the cell mem-
results from clinical interventions or accidental sodium
into the cells and restoring the cell volume)
8)
brane , whereas the source (uptake from the extra-
loading. Because sustained hypernatremia can occur
cellular fluid or production within the cells) of glu-
only when thirst or access to water is impaired, the
tamine and glutamate is at present unknown.
groups at highest risk are patients with altered mental
The cerebral adaptation in hypernatremia has two
status, intubated patients, infants, and elderly per-
important clinical consequences: Chronic hypernatremia
sons . Hypernatremia in infants usually results from
is much less likely to induce neurologic symptoms.
diarrhea, whereas in elderly persons it is usually
Assessment of symptoms attributable to hypernatremia
associated with infirmity or febrile illness12, 13). Thirst
is often difficult because most affected adults have
impairment also occurs in elderly patients . Often the
underlying neurologic disease. The latter is required to
cause is evident from the history. Measurement of
11)
14)
diminish the protective thirst mechanism that normally
prevents the development of hypernatremia, even in
patients with diabetes insipidus. Correction of chronic
hypernatremia must occur slowly to prevent rapid fluid
movement into the brain and cerebral edema, changes
that can lead to seizures and coma9). Although the
brain cells can rapidly lose potassium and sodium in
response to this cell swelling, the loss of accumulated
osmolytes occurs more slowly, a phenomenon that acts
to hold water within the cells5). The loss of myoinositol, for example, requires both a reduction in synthesis of new sodium-inositol cotransporters8) and the
activation of a specific inositol efflux mechanism in
10)
the cell membrane . The delayed clearance of osmolytes from the cell can predispose to cerebral edema
if the plasma sodium concentration is lowered too
rapidly. As a result, the rate of correction in asymptomatic patients should not exceed 12 mEq/L per day,
which represents an average of 0.5 mEq/L per hour.
Table 1. Major Causes of Hypernatremia
Euvolemic Hypernatremia (Pure water loss)
Extrarenal losses
Respiratory (tachycardia)
Dermal (sweating, fever)
Renal losses
Central diabetes insipidus
Nephrogenic diabetes insipidus
Other
Inability to gain access to fluids
Hypodipsia or adipsia
Reset osmostat (essential hypernatremia)
Hypovolemic Hypernatremia
(water Deficit in Excess of Sodium Deficit)
Extrarenal losses
Gastrointestinal losses
(e.g., diarrhea, vomiting, fistulas)
Dermal (burns, excessive sweating)
Renal losses
Osmotic diuresis (mannitol, glucose, urea)
Loop diuretics
Postobstructive diuresis
Intrinsic renal disease
Hypervolemic Hypernatremia
(Sodium gain in Excess of Water Gain)
Hypertonic saline or NaHCO3 administration
Infants or comatose patients given hypertonic feedings
Mineralocorticoid excess
68
SW Kim : Hypernatemia : Successful Treatment
urine osmolality in relation to the plasma osmolality
dissipates as the disorder progresses and is absent in
and the urine sodium concentration help if the cause is
patients with hypodipsia. The level of consciousness is
unclear (Fig. 1). Patients with diabetes insipidus pre-
correlated with the severity of the hypernatremia20).
sent with polyuria and polydipsia (and not hyperna-
Muscle weakness, confusion, and coma are sometimes
tremia unless thirst sensation is impaired). Central
manifestations of coexisting disorders rather than of
diabetes insipidus and nephrogenic diabetes insipidus
the hypernatremia itself (Table 2).
may be differentiated by the response to water depri-
Brain shrinkage induced by hypernatremia can
vation (failure to concentrate urine) followed by the
cause vascular rupture, with cerebral bleeding, sub-
V2-receptor agonist desmopressin, causing concentra-
arachnoid
tion of urine in patients with central diabetes insipidus.
damage or death. Brain shrinkage is countered by an
hemorrhage,
and
permanent
neurologic
adaptive response that is initiated promptly and conClinical manifestations
sists of solute gain by the brain that tends to restore
lost water. This response leads to the normalization of
Signs and symptoms of hypernatremia largely re-
brain volume and accounts for the milder symptoms of
flect central nervous system dysfunction and are
hypernatremia that develops slowly21). However, the
prominent when the increase in the serum sodium
normalization of brain volume does not correct hyper-
concentration is large or occurs rapidly (i.e., over a
osmolality in the brain. In patients with prolonged
15)
period of hours) . Most outpatients with hyperna16)
tremia are either very young or very old . Common
symptoms in infants include hyperpnea, muscle weakness, restlessness, a characteristic high-pitched cry,
insomnia, lethargy, and even coma. Convulsions are
typically absent except in cases of inadvertent sodium
loading or aggressive rehydration17, 18). Unlike infants,
elderly patients generally have few symptoms until the
serum sodium concentration exceeds 160 mmol per
liter19). Intense thirst may be present initially, but it
Table 2. Signs and Symptoms of Hypernatremia
Depression of sensorium
Irritability
Seizures (unusual in adults)
Focal neurologic deficits
Muscle spasticity (unusual in adults)
Signs of volume depletion (variable)
Fever
Nausea or vomiting
Labored respiration
Intense thirst
Fig. 1. Diagnostic algorithm for hypernatremia.
SW Kim : Hypernatemia : Successful Treatment
hyperosmolality, aggressive treatment with hypotonic
＋
Water deficit= CBW×(
fluids may cause cerebral edema, which can lead to
coma, convulsions, and death17, 18).
69
plasma [Na ]
140
-1)
CBW refers to estimated current body water. The
total body water is normally about 60 and 50 percent
Treatments
of lean body weight in younger men and women,
respectively, and is somewhat lower in the elderly
The primary goal in the treatment of patients with
(about 50 and 45 percent in men and women,
hypernatremia is the restoration of serum tonicity. In
respectively)23). However, it is probably reasonable to
patients with hypernatremia that has developed over a
use values about 10 percent lower (50 and 40 percent)
period of hours, rapid correction of plasma sodium
in hypernatremic patients who are water-depleted.
(falling by 1 mmol/L per hour) improves the prognosis
Thus, in a 60 kg woman with a plasma sodium
without the risk of convulsions and cerebral edema1).
concentration of 168 mEq/L, total body water is about
Management of a shocked patient needs specialist
40 percent of body weight and the water deficit can be
input and close monitoring, preferably in a high de-
approximated from :
pendency unit. Intravenous normal saline should be
used to correct the extracellular fluid depletion, with
Water deficit=0.4×60 ([168/140]-1) = 4.8 liters
calculation of the free water deficit to determine how
This formula estimates the amount of positive water
much 5% dextrose to give. In patients with hyper-
balance required to return the plasma sodium con-
natremia of longer or unknown duration, reducing the
centration to 140 mEq/L. Then, when calculating the
sodium concentration more slowly is prudent. Patients
amount of free water to give (either intravenously, as
should be given intravenous 5% dextrose for acute
dextrose in water, or orally if the patient is able to
hypernatremia or half-normal saline (0.45% sodium
drink), insensible losses and some part of urine and
chloride)
to
gastrointestinal losses must be added to the calcula-
tolerate oral water. Central diabetes insipidus is
tion. Although this formula provides an adequate
treated with desmopressin, either as intranasal spray
estimate of the water deficit in patients with hyper-
or tablets, with careful monitoring to avoid the com-
natremia caused by pure water loss, it underestimates
plications of water intoxication (delaying one dose
the deficit in patients with hypotonic fluid loss.
for
chronic
hypernatremia
if
unable
each week to allow polyuria and thirst to “breakthrough” in patients susceptible to hyponatremia with
2. Rate of correction
desmopressin may be prudent). Treatment of nephro-
There are no definitive clinical trials, but data in
genic diabetes insipidus includes removal of precipi-
children suggest that the maximum safe rate at which
tating drugs (if possible) and sometimes initiation of
the plasma sodium concentration should be lowered is
thiazide
anti-inflammatory
by 0.5 mEq/L per hour and no more than by 12
drugs, or both. The following discussion primarily
mEq/L per day24). Overly rapid correction is potentially
applies to the majority of patients in whom hyperna-
dangerous in hypernatremia (as it is in hyponatremia).
tremia is induced by water loss.
Hypernatremia initially causes fluid movement out of
diuretics,
non-steroidal
the brain and cerebral contraction that is primarily
responsible for the associated symptoms. Within one
1. Water deficit
The water deficit in the hypernatremic patient can
22, 23)
be estimated from the following formula
.
to three days, however, brain volume is largely restored due to water movement from the cerebrospinal fluid
into the brain and to the uptake of solutes by the
70
SW Kim : Hypernatemia : Successful Treatment
24)
cells . Rapidly lowering the plasma sodium concen-
with possibly catastrophic consequences. Selecting the
tration once this adaptation has occurred causes
most hypotonic infusate that is suitable for the
osmotic water movement into the brain, increasing
particular type of hypernatremia ensures the admini-
brain size above normal. This cerebral edema can then
stration of the least amount of fluid. Appropriate
lead to seizures, permanent neurologic damage, or
allowances for ongoing fluid losses must be made to
17, 18)
. This sequence of an adverse response to
prevent serious deviations in either direction from the
therapy has been primarily described in children in
targeted serum sodium concentration. Scrupulous ad-
whom the hypernatremia was corrected at a rate
herence to these management guidelines should help
death
22)
exceeding 0.7 mEq/L per h . In comparison, no neu-
prevent such complications. Most importantly, the fluid
rologic sequelae were induced if the plasma sodium
prescription should be reassessed at regular intervals
23)
concentration were lowered at 0.5 mEq/L per hour .
in the light of laboratory values and the patient’s
clinical status1).
3. Common errors in management
Isotonic saline is unsuitable for correcting hyper-
Prognosis
natremia. Consider a 50-year-old man with a serum
sodium concentration of 162 mmol per liter and a body
The morbidity and mortality of patients with acute
weight of 70 kg (estimated volume of total body
hypernatremia is very high. In children, the mortality
water, 42 liters [0.5×70]). The retention of 1 liter of 0.9
of acute hypernatremia ranges between 10 and 70%.
percent sodium chloride will decrease the serum
As many as two-thirds of the survivors have neurolo-
sodium concentration by only 0.22 mmol per liter
gic sequelae. In contrast, mortality in chronic hyper-
([154-162]÷[35＋1]=-0.22). Although the sodium con-
natremia is 10%. In adults, serum Na concentrations
centration of the infusate is lower than the patient’s
above 160 mmol/L are associated with a 75% mor-
serum sodium concentration, it is not sufficiently low
tality1). Since hypernatremia in adults occurs in the
to alter the hypernatremia substantially. Furthermore,
setting of serious disease the mortality rates may
ongoing hypotonic fluid losses might outpace the
reflect the severity of the underlying diseases rather
administration
than that of hypernatremia.
of
isotonic
saline,
aggravating
the
hypernatremia. The sole indication for administering
isotonic saline to a patient with hypernatremia is a
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